Fluorinated Benzofuran Derivatives

ABSTRACT

The invention relates to fluorinated compounds and their use in the field of pathological syndromes of the cardiovascular system. Novel fluorinated benzofuran derivatives of amiodarone and pharmaceutically acceptable salts or solvates thereof and their use for the treatment of arrhythmias are described.

RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S.provisional application Nos. 61/625,359 and 61/698,994, respectivelyfiled on Apr. 17, 2012 and Sep. 10, 2012, which are incorporated hereinby reference.

BACKGROUND

Two major types of arrhythmias are tachycardias (the heartbeat is toofast—more than 100 beats per minute), and bradycardia (the heartbeat istoo slow—less than 60 beats per minute). Arrhythmias can belife-threatening if they cause a severe decrease in the pumping functionof the heart. When the pumping function is severely decreased for morethan a few seconds, blood circulation is essentially stopped, and organdamage (such as brain damage) may occur within a few minutes. Lifethreatening arrhythmias include ventricular tachycardia and ventricularfibrillation. Amiodarone or 2-n-butyl 3-[4-(2-diethylaminoethoxy)3,5-diiodo benzoyl]benzofuran has been approved in an oral tablet form(CORDARONE®) for the treatment of life-threatening ventriculartachyarrhythmias in the United States. This drug is useful not only intreating these arrhythmias but also in treating less severe ventriculararrhythmias and many superventricular arrhythmias including atrialfibrillation and reentrant tachyarrhythmias involving accessorypathways.

Despite the beneficial activities of amiodarone, it is practicallyinsoluble or slightly soluble in an aqueous solvent. Hence, it isdifficult to formulate a dosage form suitable for administration.Furthermore, amiodarone has unwanted side effects. For example,treatment can result in hypothyroidism. Amiodarone and its des-ethylmetabolite display an undesirable prolonged residence time in tissues.Amiodarone causes phospholipidosis in the lung, which results in thedestruction of macrophages in the alveoli. This destruction is expressedin the patient undergoing treatment with amiodarone by the appearance ofpulmonary complications, such as respiratory insufficiency, whichrequire the cessation of treatment. Thus, there is a continuing need fornew compounds to treat or prevent arrhythmias and other pathologicalsyndromes of the cardiovascular system.

DETAILED DESCRIPTION OF THE INVENTION

For purposes of the present invention, the following definitions will beused (unless expressly stated otherwise):

The term “a compound of the invention” or “compounds of the invention”refers to a compound(s) disclosed herein e.g., a compound(s) of theinvention includes a compound(s) of any of the formulae described hereinincluding formulae I, II, III, IV, V, VI, VII, VIII, or IX and/or acompound(s) explicitly disclosed herein. Whenever the term is used inthe context of the present invention it is to be understood that thereference is being made to the free base and deuterium labeledcompounds, and the corresponding pharmaceutically acceptable salts orsolvates thereof, provided that such is possible and/or appropriateunder the circumstances.

The term “pharmaceutical” or “pharmaceutically acceptable” when usedherein as an adjective, means substantially non-toxic and substantiallynon-deleterious to the recipient.

By “pharmaceutical formulation” it is further meant that the carrier,solvent, excipient(s) and salt must be compatible with the activeingredient of the formulation (e.g. a compound of the invention). It isunderstood by those of ordinary skill in this art that the terms“pharmaceutical formulation” and “pharmaceutical composition” aregenerally interchangeable, and they are so used for the purposes of thisapplication.

Some of the compounds of the present invention may exist in unsolvatedas well as solvated forms such as, for example, hydrates.

“Solvate” means a solvent addition form that contains either astoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate. In the hydrates, the water moleculesare attached through secondary valencies by intermolecular forces, inparticular hydrogen bridges. Solid hydrates contain water as so-calledcrystal water in stoichiometric ratios, where the water molecules do nothave to be equivalent with respect to their binding state. Examples ofhydrates are sesquihydrates, monohydrates, dihydrates or trihydrates.Equally suitable are the hydrates of salts of the compounds of theinvention.

The invention also includes metabolites of the compounds describedherein.

Physiologically acceptable, i.e. pharmaceutically compatible, salts canbe salts of the compounds of the invention with inorganic or organicacids. Preference is given to salts with inorganic acids, such as, forexample, hydrochloric acid, hydrobromic acid, phosphoric acid orsulphuric acid, or to salts with organic carboxylic or sulphonic acids,such as, for example, acetic acid, trifluoroacetic acid, propionic acid,maleic acid, fumaric acid, malic acid, citric acid, tartaric acid,lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonicacid, benzenesulphonic acid, toluenesulphonic acid ornaphthalenedisulphonic acid.

Other pharmaceutically compatible salts which may be mentioned are saltswith customary bases, such as, for example, alkali metal salts (forexample sodium or potassium salts), alkaline earth metal salts (forexample calcium or magnesium salts) or ammonium salts, derived fromammonia or organic amines, such as, for example, diethylamine,triethylamine, ethyldiisopropylamine, procaine, dibenzylamine,N-methylmorpholine, dihydroabietylamine or methylpiperidine.

When any variable (e.g., X) occurs more than one time in any constituentor formula for a compound, its definition at each occurrence isindependent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with one or more Xmoieties, then X at each occurrence is selected independently from thedefinition of X. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compoundswithin a designated atom's normal valency.

As used herein, the term “treat,” “treating,” or “treatment” herein, ismeant decreasing the symptoms, markers, and/or any negative effects of acondition in any appreciable degree in a patient who currently has thecondition. In some embodiments, treatment may be administered to asubject who exhibits only early signs of the condition for the purposeof decreasing the risk of developing the disease, disorder, and/orcondition.

As used herein, the term “prevent,” “prevention,” or “preventing” refersto any method to partially or completely prevent or delay the onset ofone or more symptoms or features of a disease, disorder, and/orcondition. Prevention may be administered to a subject who does notexhibit signs of a disease, disorder, and/or condition.

As used herein, “subject” means a human or animal (in the case of ananimal, more typically a mammal). In one aspect, the subject is a human.In one aspect, the subject is a male. In one aspect, the subject is afemale.

As used herein, the term a “fluorinated derivative” is a derivativecompound that has the same chemical structure as the original compound,except that at least one atom is replaced with a fluorine atom or with agroup of atoms containing at least one fluorine atom.

The problem to be solved by the present invention is the identificationof novel compounds for the treatment and/or prevention of arrhythmiasand related disorders. Although drugs for arrhythmias and relateddisorders are available, these drugs are often not suitable for manypatients for a variety of reasons. For example, many of the availablearrhythmia drugs have an inconvenient or ineffective mode ofadministration. Many arrhythmia drugs are associated with adverseeffects. For example, adverse side effects may include hypothyroidism,toxic effect on brain or spinal cord function, abnormally low bloodpressure, interstitial pneumonitis, lung fibrosis, inflammation of thealveoli of the lungs, sun-sensitive skin, and abnormal liver functiontests. Further, some arrhythmia drugs display an undesirable prolongedresidence time in tissues. The present invention provides the solutionof new fluorinated benzofuran derivatives for the treatment and/orprevention of arrhythmias and related disorders. The fluorinatedcompounds described herein have the advantage of providing improvedpotency, selectivity, tissue penetration, half-life, and/or metabolicstability.

Compounds of the Invention

The present invention relates to novel fluorinated benzofuranderivatives and their use. The present invention relates the synthesisof fluorinated benzofuran derivatives.

In one aspect, the invention provides a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein X₁,X₂, X₃, and X₄ are each independently selected from hydrogen, I, F, CF₃,CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F, provided that when X₁ and X₄ areeach a hydrogen, then X₂ and X₃ are not both iodine. In one aspect, theinvention provides a compound of formula I, provided that the compoundhas at least one fluorine atom or has a group of atoms containing atleast one fluorine atom. In one aspect, the invention provides acompound of formula I, provided that at least one of X₁, X₂, X₃, and X₄is F or a group of atoms containing at least one fluorine atom.

While all of the compounds of this invention are useful, certain classesare preferred. The following paragraphs describe certain preferredclasses of a compound of formula I, wherein:

a) at least one of X₁, X₂, X₃, and X₄ is selected from F, CF₃, CHF₂,CH₂F, OCF₃, OCHF₂, and OCH₂F;b) one of X₁, X₂, X₃, and X₄ is selected from F, CF₃, CHF₂, CH₂F, OCF₃,OCHF₂, and OCH₂F;c) one of X₁, X₂, X₃, and X₄ is selected from F, CF₃, CHF₂, CH₂F, OCF₃,OCHF₂, and OCH₂F and the remaining X₁, X₂, X₃, and X₄ are selected fromF, I and hydrogen;d) two of X₁, X₂, X₃, and X₄ are selected from F, CF₃, CHF₂, CH₂F, OCF₃,OCHF₂, and OCH₂F and the remaining X₁, X₂, X₃, and X₄ are selected fromF, I and hydrogen; ande) at least one of X₁, X₂, X₃, and X₄ is selected from F, CF₃, CHF₂, andCH₂F.

In one aspect, the invention provides a compound of formula II:

or a pharmaceutically acceptable salt or solvate thereof, whereinX₂ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;X₃ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F,provided that X₂ and X₃ are not both I. In one aspect, the inventionprovides a compound of formula II, provided that the compound has atleast one fluorine atom or has a group of atoms containing at least onefluorine atom. In one aspect, the invention provides a compound offormula II, provided that at least one of X₂ and X₃ is F or a group ofatoms containing at least one fluorine atom.

The following paragraphs describe certain preferred classes of acompound of formula II, wherein:

a-1) X₂ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F andX₃ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;a-2) X₂ is CF₃ and X₃ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;a-3) X₂ is CF₃ and X₃ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;a-4) X₂ is CF₃ and X₃ is selected from CF₃, CHF₂, and CH₂F;a-5) X₂ is CF₃ and X₃ is selected from OCF₃, OCHF₂, and OCH₂F;a-6) X₂ is F and X₃ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;a-7) X₂ is F and X₃ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;a-8) X₂ is F and X₃ is selected from CF₃, CHF₂, and CH₂F;a-9) X₂ is F and X₃ is selected from OCF₃, OCHF₂, and OCH₂F;a-10) X₃ is CF₃ and X₂ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;a-11) X₃ is CF₃ and X₂ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂,and OCH₂F;a-12) X₃ is CF₃ and X₂ is selected from CF₃, CHF₂, and CH₂F;a-13) X₃ is CF₃ and X₂ is selected from OCF₃, OCHF₂, and OCH₂F;a-14) X₃ is F and X₂ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;a-15) X₃ is F and X₂ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;a-16) X₃ is F and X₂ is selected from CF₃, CHF₂, and CH₂F;a-17) X₃ is F and X₂ is selected from OCF₃, OCHF₂, and OCH₂F;a-18) X₂ is CF₃ and X₃ is selected from hydrogen, I, F, CF₃, CHF₂, andCH₂F;a-19) X₂ is CF₃ and X₃ is selected from hydrogen, I, and CF₃.a-20) X₃ is hydrogen and X₂ is selected from F, CF₃, CHF₂, CH₂F, OCF₃,OCHF₂, and OCH₂F.a-21) X₃ is hydrogen and X₂ is selected from F, CF₃, CHF₂, and CH₂F.a-22) X₃ is hydrogen and X₂ is selected from F and CF₃.

In one aspect, the invention provides a compound of formula III:

or a pharmaceutically acceptable salt or solvate thereof, whereinX₁ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F; andX₂ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F. In one aspect, the invention provides a compound of formula III,provided that the compound has at least one fluorine atom or has a groupof atoms containing at least one fluorine atom. In one aspect, theinvention provides a compound of formula III, provided that at least oneof X₁ and X₂ is F or a group of atoms containing at least one fluorineatom.

The following paragraphs describe certain preferred classes of acompound of formula III, wherein:

b-1) X₁ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F andX₂ is selected from I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;b-2) X₂ is I and X₁ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂,and OCH₂F;b-3) X₂ is I and X₁ is selected from F, CF₃, CHF₂, and CH₂F;b-4) X₁ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F andX₂ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;b-5) X₁ is CF₃ and X₂ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;b-6) X₁ is CF₃ and X₂ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;b-7) X₁ is CF₃ and X₂ is selected from CF₃, CHF₂, and CH₂F;b-8) X₁ is CF₃ and X₂ is selected from OCF₃, OCHF₂, and OCH₂F;b-9) X₁ is F and X₂ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;b-10) X₁ is F and X₂ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;b-11) X₁ is F and X₂ is selected from CF₃, CHF₂, and CH₂F;b-12) X₁ is F and X₂ is selected from OCF₃, OCHF₂, and OCH₂F;b-13) X₂ is CF₃ and X₁ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;b-14) X₂ is CF₃ and X₁ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂,and OCH₂F;b-15) X₂ is CF₃ and X₁ is selected from CF₃, CHF₂, and CH₂F;b-16) X₂ is CF₃ and X₁ is selected from OCF₃, OCHF₂, and OCH₂F;b-17) X₂ is F and X₁ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;b-18) X₂ is F and X₁ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;b-19) X₂ is F and X₁ is selected from CF₃, CHF₂, and CH₂F; andb-20) X₂ is F and X₁ is selected from OCF₃, OCHF₂, and OCH₂F;

In one aspect, the invention provides a compound of formula IV:

or a pharmaceutically acceptable salt or solvate thereof, whereinX₂ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F; andX₄ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F. In one aspect, the invention provides a compound of formula IV,provided that the compound has at least one fluorine atom or has a groupof atoms containing at least one fluorine atom. In one aspect, theinvention provides a compound of formula IV, provided that at least oneof X₂ and X₄ is F or a group of atoms containing at least one fluorineatom.

The following paragraphs describe certain preferred classes of acompound of formula IV, wherein:

c-1) X₂ is selected from I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂Fand X₄ is selected from I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;c-2) X₂ is I and X₄ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂,and OCH₂F;c-3) X₂ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F andX₄ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;c-4) X₂ is CF₃ and X₄ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;c-5) X₂ is CF₃ and X₄ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;c-6) X₂ is CF₃ and X₄ is selected from CF₃, CHF₂, and CH₂F;c-7) X₂ is CF₃ and X₄ is selected from OCF₃, OCHF₂, and OCH₂F;c-8) X₂ is F and X₄ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;c-9) X₂ is F and X₄ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;c-10) X₂ is F and X₄ is selected from CF₃, CHF₂, and CH₂F;c-11) X₂ is F and X₄ is selected from OCF₃, OCHF₂, and OCH₂F;c-12) X₄ is CF₃ and X₂ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;c-13) X₄ is CF₃ and X₂ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂,and OCH₂F;c-14) X₄ is CF₃ and X₂ is selected from CF₃, CHF₂, and CH₂F;c-15) X₄ is CF₃ and X₂ is selected from OCF₃, OCHF₂, and OCH₂F;c-16) X₄ is F and X₂ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;c-17) X₄ is F and X₂ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;c-18) X₄ is F and X₂ is selected from CF₃, CHF₂, and CH₂F; andc-19) X₄ is F and X₂ is selected from OCF₃, OCHF₂, and OCH₂F.

In one aspect, the invention provides a compound of formula V:

or a pharmaceutically acceptable salt or solvate thereof, whereinX₁ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F; andX₄ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F. In one aspect, the invention provides a compound of formula V,provided that the compound has at least one fluorine atom or has a groupof atoms containing at least one fluorine atom. In one aspect, theinvention provides a compound of formula V, and provided that at leastone of X₁ and X₄ is F or a group of atoms containing at least onefluorine atom.

The following paragraphs describe certain preferred classes of acompound of formula V,

wherein:d-1) X₁ is selected from I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂Fand X₄ is selected from I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;d-2) X₁ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F andX₄ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;d-3) X₁ is CF₃ and X₄ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;d-4) X₁ is CF₃ and X₄ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;d-5) X₁ is CF₃ and X₄ is selected from CF₃, CHF₂, and CH₂F;d-6) X₁ is CF₃ and X₄ is selected from OCF₃, OCHF₂, and OCH₂F;d-7) X₁ is F and X₄ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;d-8) X₁ is F and X₄ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;d-9) X₁ is F and X₄ is selected from CF₃, CHF₂, and CH₂F;d-10) X₁ is F and X₄ is selected from OCF₃, OCHF₂, and OCH₂F;d-11) X₄ is CF₃ and X₁ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;d-12) X₄ is CF₃ and X₁ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂,and OCH₂F;d-13) X₄ is CF₃ and X₁ is selected from CF₃, CHF₂, and CH₂F;d-14) X₄ is CF₃ and X₁ is selected from OCF₃, OCHF₂, and OCH₂F;d-15) X₄ is F and X₁ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;d-16) X₄ is F and X₁ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;d-17) X₄ is F and X₁ is selected from CF₃, CHF₂, and CH₂F; andd-18) X₄ is F and X₁ is selected from OCF₃, OCHF₂, and OCH₂F.

In one aspect, the invention provides a compound of formula VI:

or a pharmaceutically acceptable salt or solvate thereof, whereinX₁ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F; andX₄ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F. In one aspect, the invention provides a compound of formula VI,provided that at least one fluorine atom or has a group of atomscontaining at least one fluorine atom. In one aspect, the inventionprovides a compound of formula VI, provided that at least one of X₁ andX₃ is F or a group of atoms containing at least one fluorine atom

The following paragraphs describe certain preferred classes of acompound of formula VI, wherein:

e-1) X₁ is selected from I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂Fand X₃ is selected from I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;e-2) X₃ is I and X₁ is selected from I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂,and OCH₂F;e-3) X₁ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F andX₃ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;e-4) X₁ is CF₃ and X₃ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;e-5) X₁ is CF₃ and X₃ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;e-6) X₁ is CF₃ and X₃ is selected from CF₃, CHF₂, and CH₂F;e-7) X₁ is CF₃ and X₃ is selected from OCF₃, OCHF₂, and OCH₂F;e-8) X₁ is F and X₃ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;e-9) X₁ is F and X₃ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;e-10) X₁ is F and X₃ is selected from CF₃, CHF₂, and CH₂F;e-11) X₁ is F and X₃ is selected from OCF₃, OCHF₂, and OCH₂F;e-12) X₃ is CF₃ and X₁ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;e-13) X₃ is CF₃ and X₁ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂,and OCH₂F;e-14) X₃ is CF₃ and X₁ is selected from CF₃, CHF₂, and CH₂F;e-15) X₃ is CF₃ and X₁ is selected from OCF₃, OCHF₂, and OCH₂F;e-16) X₃ is F and X₁ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F;e-17) X₃ is F and X₁ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F;e-18) X₃ is F and X₁ is selected from CF₃, CHF₂, and CH₂F; ande-19) X₃ is F and X₁ is selected from OCF₃, OCHF₂, and OCH₂F.

In one aspect, the invention provides a compound of formula VII:

or a pharmaceutically acceptable salt or solvate thereof, whereinX₂ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F.

The following paragraphs describe certain preferred classes of acompound of formula VII, wherein:

f-1) X₂ is selected from F, CF₃, CHF₂, and CH₂F;f-2) X₂ is selected from F and CF₃;f-3) X₂ is selected from CF₃, CHF₂, and CH₂F;f-4) X₂ is selected from F, OCF₃, OCHF₂, and OCH₂F;f-5) X₂ is selected from F and OCF₃; andf-6) X₂ is selected from OCF₃, OCHF₂, and OCH₂F.

In one aspect, the invention provides a compound of formula VIII:

or a pharmaceutically acceptable salt or solvate thereof, whereinX₂ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F.

The following paragraphs describe certain preferred classes of acompound of formula VIII, wherein:

g-1) X₂ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;g-2) X₂ is selected from F, CF₃, CHF₂, and CH₂F;g-3) X₂ is selected from F and CF₃;g-4) X₂ is selected from CF₃, CHF₂, and CH₂F;g-5) X₂ is selected from F, OCF₃, OCHF₂, and OCH₂F;g-6) X₂ is selected from F and OCF₃; andg-7) X₂ is selected from OCF₃, OCHF₂, and OCH₂F.

In one aspect, the invention provides a compound of formula IX:

or a pharmaceutically acceptable salt or solvate thereof, whereinX₁ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;

The following paragraphs describe certain preferred classes of acompound of formula IX, wherein:

h-1) X₁ is selected from CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;h-2) X₁ is selected from F, CF₃, CHF₂, and CH₂F;h-3) X₁ is selected from F and CF₃;h-4) X₁ is selected from CF₃, CHF₂, and CH₂F;h-5) X₁ is selected from F, OCF₃, OCHF₂, and OCH₂F;h-6) X₁ is selected from F and OCF₃; andh-7) X₁ is selected from OCF₃, OCHF₂, and OCH₂F.

In one aspect, the invention provides a compound of Table 1.

TABLE 1 Compound # 1

2

3

4

5

6

7

8

9

10

11

12

13

14

In one aspect, a compound of the invention is a pharmaceuticallyacceptable salt. In one aspect, a compound of the invention is asolvate. In one aspect, a compound of the invention is a hydrate.

The present invention relates to pharmaceutical compositions comprisingone of the compounds of the invention as an active ingredient. In oneaspect, the invention provides a pharmaceutical composition comprisingat least one compound of formulae I, II, III, IV, V, VI, VII, VIII, orIX or a pharmaceutically acceptable salt or solvate thereof and one ormore pharmaceutically acceptable carrier or excipient. In one aspect,the invention provides a pharmaceutical composition comprising at leastone compound of Table 1.

The present invention relates to a method of synthesizing a compound ofthe invention or a pharmaceutically acceptable salt or solvate thereof.A compound of the invention can be synthesized using a variety ofmethods known in the art. The scheme and description below depicts somegeneral routes for the preparation of a compound of the invention.

Scheme 1A outlines a preparation for a compound of Formula I. It isunderstood that Formulae II, III, IV, V, VI, VII, VIII, and IX describedherein are subsets of Formula I. Thus, the preparations described for acompound of Formula I can also be applied for the preparation of acompound of Formulae II, III, IV, V, VI, VII, VIII, and IX.

In Scheme 1A, the preparation begins with Compound A. Compounds such asCompound A are commercially available, for example the compound whereinX_(a) is H is available from multiple chemical supply sources. In Step1, the hydroxyl group of Compound A is protected with a suitableprotecting group (PG) to form Compound B. For example, the hydroxylgroup of Compound A can be treated with pyridine-acetic anhydride andDMAP, to form compound B, where PG is acetyl. Examples of additionalprotecting groups are described by T. W. Greene, “Protective Groups inOrganic Synthesis”, John Wiley and Sons, New York, N.Y., Fourth Edition.In Step 1, after protection of the hydroxyl group, at least one X_(a) ofCompound A is converted to a fluorine atom or a fluorine containinggroup. For example, at least one X_(a) of Compound A can be an iodineatom that is converted to fluorine or a fluorine containing group toform Compound B. Compound A can be treated with methylfluorosulfonyldifluoroacetate and CuI to form Compound B, such that oneX_(a) is converted to the fluorine containing group is CF₃. It is notedthat one or more X_(a) of Compound A may not change in Step 1 e.g.,X_(a) is X₁, wherein X₁ is hydrogen.

In Step 2, PG of Compound B is deprotected and the resulting hydroxylgroup is alkylated to form a compound of Formula I. PG can bedeprotected using a variety of conditions known in the art. In oneaspect, the deprotection conditions can be basic. For example, when PGis acetyl, PG can be deprotected using potassium carbonate and methanol.The deprotected hydroxyl group can be alkylated using a variety ofdifferent methods to form a compound of Formula I. For example, thehydroxyl group can be alkylated with 2-chloro-N,N-diethylanamine usingNaI and K₂CO₃.

If any or more of X₁, X₂, X₃, or X₄ of Compound B is an iodine atom, theiodine atom can be replaced with a hydrogen atom. For example, theiodine atom can be reduced using zinc powder in acetic acid.

If one of the X_(a) of Compound A contains a fluorine atom or a fluorinecontaining group, the hydroxyl group of Compound A can be directlyalkylated to form a compound of Formula I. For example, Compound A canbe alkylated with 2-chloro-N,N-diethylanamine using NaI and K₂CO₃ asreagents to form compound C.

The present invention also comprehends deuterium labeled compounds,which are identical to those recited in formulae I, II, III, IV, V, VI,VII, VIII, or IX and the compounds listed in Table 1 but for the factthat one or more hydrogen atoms is replaced by a deuterium atom havingan abundance of deuterium at that position that is substantially greaterthan the natural abundance of deuterium, which is 0.015%.

The term “deuterium enrichment factor” as used herein means the ratiobetween the deuterium abundance and the natural abundance of adeuterium. In one aspect, a compound of the invention has a deuteriumenrichment factor for each deuterium atom of at least 3500 (52.5%deuterium incorporation at each deuterium atom), at least 4000 (60%deuterium incorporation), at least 4500 (67.5% deuterium incorporation),at least 5000 (75% deuterium), at least 5500 (82.5% deuteriumincorporation), at least 6000 (90% deuterium incorporation), at least6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuteriumincorporation), at least 6600 (99% deuterium incorporation), or at least6633.3 (99.5% deuterium incorporation).

A compound of the invention or a pharmaceutically acceptable salt orsolvate thereof that contains the aforementioned deuterium atom(s) iswithin the scope of the invention. Further, substitution with heavierdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements.

In one aspect, the invention provides a deuterium labeled compound ofTable 2.

TABLE 2 Compound # 15

In one aspect, a deuterium labeled compound of the invention is apharmaceutically acceptable salt. In one aspect, a deuterium labeledcompound of the invention is a solvate. In one aspect, a deuteriumlabeled compound of the invention is a hydrate.

The present invention relates to pharmaceutical compositions comprisingone of the deuterium labeled compounds of the invention as an activeingredient. In one aspect, the invention provides a pharmaceuticalcomposition comprising at least one deuterium labeled compound offormulae I, II, III, IV, V, VI, VII, VIII, or IX or a pharmaceuticallyacceptable salt or solvate thereof and one or more pharmaceuticallyacceptable carrier or excipient. In one aspect, the invention provides apharmaceutical composition comprising at least one compound of Table 2.

The present invention relates to a method of synthesizing a deuteriumlabeled compound of the invention or a pharmaceutically acceptable saltor solvate thereof.

The deuterium labeled compounds of the invention can be prepared usingany of a variety of art-recognized techniques. The deuterium labeledcompounds can generally be prepared by carrying out the proceduresdisclosed in Scheme 1A and the description provided herein for thepreparation of a compound of Formula I. For example, a deuterium labeledcompound can be prepared by starting with deuterium labeled Compound Aand/or substituting a readily available deuterium labeled reagent for anon-deuterium labeled reagent.

Methods of Use

The present invention relates to methods for the use of compounds of theinvention. The compounds of the invention have a useful pharmacologicalactivity spectrum and are therefore particularly suitable for theprophylaxis and/or treatment of disorders.

The present invention provides the use of a compound of the inventionfor the preparation of a medicament for administration to a subject foruse in the treatment or prevention of disorders.

In one aspect, the invention relates to methods for use in the treatmentor prevention of arrhythmias, including tachycardias and bradycardia,and/or other conditions including less severe ventricular arrhythmiasand many superventricular arrhythmias including atrial fibrillation andreentrant tachyarrhythmias involving accessory pathways.

In one aspect, the invention provides a method of treating or preventinga pathological syndrome of the cardiovascular system in a subjectcomprising administering to a subject in need thereof an effectiveamount of a compound of the invention or a pharmaceutically acceptablesalt thereof.

In one aspect, the invention provides a method for the treatment orprevention of cardiac arrhythmias, the potentialities offered by delayedconduction of the electrical impulse at the cardiac cell or theprolongation of the refractory period.

Although many physiopathological states prolong the repolarization ofthe cardiac cell and are associated with a reduced incidence of cardiacfibrillation, the concept of pharmacological control of rhythmicdisorders by increasing the action potential is relatively new.

The action potential of the myocardiac cell in fact represents amodification of the resting potential of this cell which, after havingattained the threshold potential (−70 millivolts) sufficiently rapidly,initiates a sequence of changes in the membrane potential.

After passage of the impulse, the myocardium remains transientlyinsensitive to a new stimulation; during the absolute refractory periodit is absolutely impossible to excite the myocardium whereas during therelative refractory period a sufficiently powerful stimulus can lead toa slowly propagated response. The existence of the refractory periodsdetermines the unidirectional nature of the propagation of the impulse.

The characteristics of the action potential determine those of theconduction and the refractory periods. Consequently, any shortening ofthe repolarization is arrhythmogenic as a result of the concomitantshortening of the refractory period. Conversely, any interferenceuniformly lengthening the action potential produces a lengthening of theabsolute refractory period and this diminishes the arythmogenicity.

In other words, if the attainment of a threshold level of the membranepotential necessary to generate a second action potential is delayed, inresponse to a stimulus, by interfering in processes which normallycontrol the rate of repolarization, the refractory periods (absoluteperiod and efficacious period) of the cardiac muscle ought to becorrespondingly prolonged, a phenomenon which would be expected tocreate an antiarrhythmic mechanism.

At present, amiodarone or 2-n-butyl 3-[4-(2-diethylamino ethoxy)3,5-diiodo benzoyl]benzofuran is one of the rare anti-arrhythmic agentson the market which possesses the properties explained above.

The compound, in fact, prolongs the repolarization plateau withoutmodifying the rate of rapid depolarization. Its anti-arrhythmic effectderives from the uniform lengthening of the action potentials and therefractory periods of the myocardial cells.

Furthermore, amiodarone possesses incomplete antiadrenergic propertiesof the α- and β-types. Hence, this compound may be considered not as aβ-blocker but as an adreno-decelerator, i.e. as a partial antagonist ofα- and β-adrenergic reactions. Such properties are of indisputablebenefit since it appears desirable not to look for complete α- orβ-antagonistic properties in view of the side effects to which they maylead in the clinic (“Bruxelles Medical”, No. 9, September 1969, pages543-560).

In one aspect, a compound of the invention possesses remarkablepharmacological properties which are expressed in particular by anincrease in the duration of the action potential and the refractoryperiods of the cardiac cell.

Amiodarone possess unwanted side effects. In particular, it is knownthat amiodarone causes phospholipidoses in the lung, which results inthe destruction of macrophages in the alveoli. This destruction isexpressed in the patient undergoing treatment with amiodarone by theappearance of pulmonary complications, such as respiratory insufficiencywhich will require the cessation of treatment. In one aspect, a compoundof the invention possesses fewer side effects than amiodarone.

In one aspect, the invention provides a method of treating or preventingarrhythmias in a subject comprising administering to the subject in needthereof an effective amount of a compound of the invention or apharmaceutically acceptable salt thereof. There are two major types ofarrhythmias are tachycardias (the heartbeat is too fast—more than 100beats per minute), and bradycardia (the heartbeat is too slow—less than60 beats per minute). Arrhythmias can be life-threatening if they causea severe decrease in the pumping function of the heart. When the pumpingfunction is severely decreased for more than a few seconds, bloodcirculation is essentially stopped, and organ damage (such as braindamage) may occur within a few minutes. Life threatening arrhythmiasinclude ventricular tachycardia and ventricular fibrillation.

Arrhythmias are identified by where they occur in the heart (atria orventricles) and by what happens to the heart's rhythm when they occur.

Arrhythmias that start in the atria are called atrial orsupraventricular (above the ventricles) arrhythmias. Ventriculararrhythmias begin in the ventricles. Ventricular arrhythmias are usuallycaused by heart disease are very serious.

Arrhythmias Originating in the Atria include:

1. Atrial fibrillation: In atrial fibrillation, the electrical activityof the heart is uncoordinated, with electricity traveling about theupper chambers in a chaotic fashion, causing the upper chambers toquiver (like a “bag of worms”) and contract inefficiently or not at all.Atrial fibrillation is common particularly in the elderly and those withheart disease. It is also common in patients with heart valve diseasewho may require surgery to repair or replace the mitral valve.2. Atrial flutter: Atrial flutter causes a rapid but coordinatedelectrical stimulation of the upper chamber of the heart, often leadingto a rapid pulse. The atria are stimulated so quickly that they cannotcontract or squeeze. This arrhythmia is due to a loop of electricity inthe upper chambers of the heart.3. Supraventricular tachycardias (PSVT): This is a fast heart rhythmsfrom the top part of the heart. In this condition, repeated periods ofvery fast heartbeats begin and end suddenly. These arrhythmias areusually due to extra connections between the upper and lower chambers ofthe heart. They are often difficult to control with medication.4. Wolff-Parkinson-White syndrome: This is a special type of Paroxysmalsupraventricular tachycardia (PSVT). This syndrome involves episodes ofa rapid heart rate (tachycardia) caused by abnormal electricalconnection in the heart. In people with Wolff-Parkinson-White syndrome,there is an extra (accessory) connection between the top and bottomchambers of the heart. Wolff-Parkinson-White occurs in approximately 4out of 100,000 people, and is one of the most common causes of fastheart rate disorders (tachyarrhymthmias) in infants and children.5. Premature supraventricular contraction or premature atrialcontraction (PAC): Premature beats or extra beats frequently causeirregular heart rhythms. Those that start in the upper chambers arecalled premature atrial contractions (PACs). These are quite common andare benign.6. Sick sinus syndrome: The sinus node (heart's pacemaker) does not fireits signals properly, so that the heart rate slows down. Sometimes therate changes back and forth between a slow (bradycardia) and fast(tachycardia) rate. This most often occurs in the elderly as a result ofdegenerative changes to the conduction pathways of the heart.7. Sinus arrhythmia: Cyclic changes in the heart rate during breathing.Common in children and often found in normal, healthy adults. In oneaspect, a pacemaker may be required for treatment.8. Sinus tachycardia: The sinus node sends out electrical signals fasterthan usual, speeding up the heart rate. This is a normal response toexercise.9. Multifocal atrial tachycardia: In multifocal atrial tachycardia(M.A.T.), multiple locations within the atria “fire” and initiate anelectrical impulse. Most of these impulses are conducted to theventricles, leading to a rapid heart rate, anywhere from 100 to 250beats per minute. M.A.T. is most common in people 50 years old and overand it is often seen in patients with lung disease.

Arrhythmias Originating in the Ventricles include:

1. Premature ventricular contraction (PVC): An electrical signal fromthe ventricles causes an early heartbeat that generally goes unnoticed.The heart then seems to pause until the next beat of the ventricleoccurs in a regular fashion. These are commonly detected in normal,healthy adults.2. Ventricular Fibrillation is where electrical signals in theventricles fire in a very fast and uncontrolled manner. This causes thelower chambers to quiver, and not pump blood. If the person does notreceive immediate medical attention and a normal rhythm is not restoredquickly, the patient will suffer brain and heart damage and die.Patients who survive this should have a defibrillator (ICD) implanted.3. Ventricular Tachycarida is a rapid, regular heartbeat arising in theventricles, the bottom chamber of the heart. When it occurs, it'susually fatal. About 400,000 people a year die from it. One treatmentchoice for this invariably includes an implantable defibrillator and ormedication and or interventions like ablation to try to minimize orlimit the number of shocks.

In aspect, the invention provides a compound of the invention that isuseful in the treatment of acute life-threatening arrhythmias and/or thechronic suppression of arrhythmias. In one aspect, a compound of theinvention is useful in supraventricular arrhythmias and/or ventriculararrhythmias.

In one aspect, a compound of the invention is useful for treatingshock-refractory ventricular fibrillation. In one aspect, a compound ofthe invention is useful for treating ventricular tachycardia.

In one aspect, the invention provides a method of treating or preventingangina pectoris in a subject comprising administering to the subject inneed thereof an effective amount of a compound of the invention or apharmaceutically acceptable salt thereof.

In one aspect, the invention provides a method of treating or preventinghypertension in a subject comprising administering to the subject inneed thereof an effective amount of a compound of the invention or apharmaceutically acceptable salt thereof.

In one aspect, the invention provides a method treating or preventingcerebral circulatory insufficiency in a subject comprising administeringto the subject in need thereof an effective amount of a compound of theinvention or a pharmaceutically acceptable salt thereof.

In one aspect, the invention provides a method of treating or preventinga pathological syndrome of the cardiovascular system, wherein thesubject is a human.

The pharmaceutical compositions of the invention may be made availablein any form suitable for administration in human therapy. As regards thedosage unit, this latter may take the form, for example, of a tablet, asugar-coated tablet, a capsule, a gelatin capsule, a powder, asuspension or a syrup for oral administration, a suppository for rectaladministration and a solution or suspension for parenteraladministration.

The dosage units of the pharmaceutical compositions of the invention maycomprise, for example, from 50 to 500 mg by weight of the activeingredient for oral administration, from 50 to 200 mg of activeingredient for rectal administration and from 50 to 150 mg of activeingredient for parenteral administration.

Depending on the route of administration selected, the pharmaceuticalcompositions of the invention are prepared by combining at least one ofthe compounds of the invention or a pharmaceutically acceptable salt orsolvate thereof with a suitable excipient, which latter may beconstituted for example by at least one ingredient selected from thefollowing substances: lactose, starches, talc, magnesium stearate,polyvinylpyrrolidone, alginic acid, collodal silica, distilled water,benzyl alcohol or sweetening agents.

In one aspect, the invention provides a medical device containing acompound of the invention or a pharmaceutically acceptable salt orsolvate thereof. In one aspect, the device is a stent.

The following Examples are illustrative and should not be interpreted inany way so as to limit the scope of the invention.

EXAMPLES Example 1 Synthesis of(2-butylbenzofuran-3-yl)(4-(2-(diethylamino)ethoxy)-3,5-bis(trifluoromethyl)phenyl)methanone(1) 4-(2-butylbenzofuran-3-carbonyl)-2-iodo-6-(trifluoromethyl)phenylacetate and4-(2-butylbenzofuran-3-carbonyl)-2,6-bis(trifluoromethyl)phenyl acetate

Under air, to(2-butylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (2.0 g,3.7 mmol, 1.0 equiv) in pyridine-Ac₂O (6 mL-6 mL) at 23° C. was addedDMAP (22 mg, 0.18 mmol, 0.050 equiv). After stirring for 40 min at 23°C., 2N HCl (50 mL) was added and the solution was extracted with EtOAc(3×20 mL). The combined organic phases were washed with brine (30 mL)and dried (Na₂SO₄). The filtrate was concentrated in vacuo to afford 2.0g of the crude acetate as yellow oil, which was used in the next stepwithout further purification. Under nitrogen, to the crude acetate (<3.7mmol, 1.0 equiv) in DMF (10 mL) was added CuI (1.8 g, 9.3 mmol, 2.5equiv) and methyl fluorosulfonyldifluoroacetate (4.7 mL, 37 mmol, 10equiv). After stirring for 40 min at 80° C., the reaction mixture wascooled to 23° C. and the precipitates were removed by filtration. Thefiltrate was concentrated in vacuo and H₂O-EtOAc (50 mL-10 mL) wasadded. The phases were separated and the aqueous phase was extractedwith EtOAc (3×10 mL). The combined organic phases were washed with brine(30 mL) and dried (MgSO₄). The filtrate was concentrated in vacuo andthe residue was purified by chromatography on silica gel eluting withhexanes/EtOAc to afford 843 mg of4-(2-butylbenzofuran-3-carbonyl)-2-iodo-6-(trifluoromethyl)phenylacetate as colorless oil (43% yield, 2 steps) and 520 mg of4-(2-butylbenzofuran-3-carbonyl)-2,6-bis(trifluoromethyl)phenyl acetateas colorless oil (30% yield, 2 steps).

4-(2-butylbenzofuran-3-carbonyl)-2-iodo-6-(trifluoromethyl)phenylacetate

R_(f)=0.50 (hexanes/EtOAc 9:1 (v/v)). NMR Spectroscopy: ¹H NMR (300 MHz,CDCl₃, 23° C., δ): 8.46 (d, J=1.8 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.51(d, J=7.8 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.33 (dd, J=7.8 Hz, 7.5 Hz,1H), 7.25 (dd, J=7.8 Hz, 7.5 Hz, 1H), 2.88 (t, J=8.1 Hz, 2H), 2.43 (s,3H), 1.85-1.70 (m, 2H), 1.42-1.30 (m, 2H), 0.92 (t, J=7.2 Hz, 3H). ¹⁹FNMR (281 MHz, CDCl₃, 23° C., δ): −61.33 (m, 3F).

4-(2-butylbenzofuran-3-carbonyl)-2,6-bis(trifluoromethyl)phenyl acetate

R_(f)=0.65 (hexanes/EtOAc 9:1 (v/v)). NMR Spectroscopy: ¹H NMR (300 MHz,CDCl₃, 23° C., δ): 8.33 (s, 2H), 7.50 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.5Hz, 1H), 7.33 (dd, J=7.8 Hz, 7.5 Hz, 1H), 7.25 (dd, J=7.8 Hz, 7.5 Hz,1H), 2.89 (t, J=8.1 Hz, 2H), 2.40 (s, 3H), 1.85-1.70 (m, 2H), 1.42-1.30(m, 2H), 0.92 (t, J=7.2 Hz, 3H). ¹⁹F NMR (281 MHz, CDCl₃, 23° C., δ):−61.03 (m, 6F).

(2-butylbenzofuran-3-yl)(4-(2-(diethylamino)ethoxy)-3,5-bis(trifluoromethyl)phenyl)methanone(1)

Under air, to4-(2-butylbenzofuran-3-carbonyl)-2,6-bis(trifluoromethyl)phenyl acetate(22 mg, 0.047 mmol, 1.00 equiv) in MeOH (0.5 mL) at 23° C. was addedK₂CO₃ (19 mg, 0.14 mmol, 3.0 equiv). After stirring for 1 h at 23° C.,the reaction mixture was concentrated in vacuo and the residue was added1N HCl (1 mL) and CH₂Cl₂ (1 mL). The phases were separated and theaqueous phase was extracted with CH₂Cl₂ (3×1 mL). The combined organicphases were washed with brine (3 mL) and dried (MgSO₄). The filtrate wasconcentrated in vacuo to afford 17 mg of the crude phenol as colorlessoil, which was used in the next step without further purification.

Under air, to the crude phenol (<0.047 mmol, 1.0 equiv) in toluene-H₂O(0.8 mL-0.4 mL) at 23° C. was added NaI (0.7 mg, 0.005 mmol, 0.1 equiv),K₂CO₃ (26 mg, 0.19 mmol, 4.0 equiv), and 2-chloro-N,N-diethylethanamine(8.9 mg, 0.052 mmol, 1.1 equiv). After stirring for 45 min at 100° C.,the reaction mixture was cooled to 23° C. and CH₂Cl₂ (0.5 mL) was added.The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (3×0.5 mL). The combined organic phases were washed with brine (1mL) and dried (MgSO₄). The filtrate was concentrated in vacuo and theresidue was purified by preparative TLC eluting with hexanes/EtOAc 1:1(v/v) to afford 14 mg of the title compound as colorless oil (56% yield,2 steps). R_(f)=0.70 (hexanes/EtOAc 3:7 (v/v)). 8.30 (s, 2H), 7.49 (d,J=7.8 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.33 (dd, J=7.8 Hz, 7.5 Hz, 1H),7.25 (dd, J=7.8 Hz, 7.5 Hz, 1H), 4.23 (t, J=6.0 Hz, 2H), 3.04 (t, J=6.0Hz, 2H), 2.87 (t, J=8.1 Hz, 2H), 2.71 (q, J=6.9 Hz, 4H), 1.82-1.70 (m,2H), 1.41-1.30 (m, 2H), 1.11 (t, J=6.9 Hz, 6H), 0.90 (t, J=7.2 Hz, 3H).¹⁹F NMR (281 MHz, CDCl₃, 23° C., δ): −61.02 (m, 6F).

Example 2 Synthesis of(2-butylbenzofuran-3-yl)(4-(2-(diethylamino)ethoxy)-3-iodo-5-(trifluoromethyl)phenyl)methasone(2)

Under air, to4-(2-butylbenzofuran-3-carbonyl)-2-iodo-6-(trifluoromethyl)phenylacetate (14 mg, 0.027 mmol, 1.00 equiv), prepared in Example 1, in MeOH(0.5 mL) at 23° C. was added K₂CO₃ (11 mg, 0.081 mmol, 3.0 equiv). Afterstirring for 1 h at 23° C., the reaction mixture was concentrated invacuo and the residue was added 1N HCl (1 mL) and CH₂Cl₂ (1 mL). Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(3×1 mL). The combined organic phases were washed with brine (3 mL) anddried (MgSO₄). The filtrate was concentrated in vacuo to afford 13 mg ofthe crude phenol as colorless oil, which was used in the next stepwithout further purification.

Under air, to the crude phenol (<0.027 mmol, 1.0 equiv) in toluene-H₂O(0.6 mL-0.3 mL) at 23° C. was added NaI (0.4 mg, 0.003 mmol, 0.1 equiv),K₂CO₃ (15 mg, 0.11 mmol, 4.0 equiv), and 2-chloro-N,N-diethylethanamine(5.1 mg, 0.030 mmol, 1.1 equiv). After stirring for 2 h at 100° C., thereaction mixture was cooled to 23° C. and CH₂Cl₂ (0.5 mL) was added. Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(3×0.5 mL). The combined organic phases were washed with brine (1 mL)and dried (MgSO₄). The filtrate was concentrated in vacuo and theresidue was purified by preparative TLC eluting with hexanes/EtOAc 1:1(v/v) to afford 10 mg of the title compound as colorless oil (63% yield,2 steps). R_(f)=0.40 (hexanes/EtOAc 1:1 (v/v)). ¹H NMR (300 MHz, CDCl₃,23° C., δ): 8.44 (d, J=1.8 Hz, 1H), 8.07 (d, J=1.8 Hz, 1H), 7.50 (d,J=7.8 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.32 (dd, J=7.8 Hz, 7.5 Hz, 1H),7.24 (dd, J=7.8 Hz, 7.5 Hz, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.07 (t, J=6.0Hz, 2H), 2.86 (t, J=8.1 Hz, 2H), 2.71 (q, J=6.9 Hz, 4H), 1.82-1.72 (m,2H), 1.41-1.31 (m, 2H), 1.11 (t, J=6.9 Hz, 6H), 0.91 (t, J=7.2 Hz, 3H).¹⁹F NMR (281 MHz, CDCl₃, 23° C., δ): −61.91 (m, 3F).

Example 3 Synthesis of(2-butylbenzofuran-3-yl)(4-(2-(diethylamino)ethoxy)-3-(trifluoromethyl)phenyl)methanone(3)(2-butylbenzofuran-3-yl)(4-hydroxy-3-(trifluoromethyl)phenyl)methanone

Under air, to4-(2-butylbenzofuran-3-carbonyl)-2-iodo-6-(trifluoromethyl)phenylacetate (1.8 g, 3.4 mmol, 1.0 equiv), prepared in Example 1, in MeOH (10mL) at 23° C. was added K₂CO₃ (1.4 g, 10 mmol, 3.0 equiv). Afterstirring for 1.5 h at 23° C., the reaction mixture was concentrated invacuo and the residue was added 1N HCl (15 mL) and CH₂Cl₂ (15 mL). Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(3×10 mL). The combined organic phases were washed with brine (30 mL)and dried (MgSO₄). The filtrate was concentrated in vacuo to afford 1.7g of the crude phenol as colorless oil, which was used in the next stepwithout further purification.

Under air, to the crude phenol (<3.4 mmol, 1.0 equiv) in AcOH (10 mL) at23° C. was added Zn powder (6.5 g, 10 mmol, 30 equiv). After stirringfor 1 hr at 23° C., the reaction mixture was filtered. The filtrate wasconcentrated in vacuo and the residue was purified by chromatography onsilica gel eluting with hexanes/EtOAc to afford 550 mg of the titlecompound as yellow oil (45% yield, 2 steps). R_(f)=0.75 (hexanes/EtOAc1:1 (v/v)). NMR Spectroscopy: ¹H NMR (300 MHz, CDCl₃, 23° C., δ): 8.09(d, J=1.8 Hz, 1H), 7.94 (dd, J=8.7 Hz, 1.8 Hz, 1H), 7.49 (d, J=7.8 Hz,1H), 7.34 (d, J=7.5 Hz, 1H), 7.26 (dd, J=7.8 Hz, 7.5 Hz, 1H), 7.21 (dd,J=7.8 Hz, 7.5 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 2.90 (t, J=8.1 Hz, 2H),1.83-1.70 (m, 2H), 1.41-1.30 (m, 2H), 0.90 (t, J=7.2 Hz, 3H). ¹⁹F NMR(281 MHz, CDCl₃, 23° C., δ): −61.62 (m, 3F).

(2-butylbenzofuran-3-yl)(4-(2-(diethylamino)ethoxy)-3-(trifluoromethyl)phenyl)methanone(3)

Under air,(2-butylbenzofuran-3-yl)(4-hydroxy-3-(trifluoromethyl)phenyl)methanone(82 mg, 0.23 mmol, 1.0 equiv) in toluene-H₂O (1.2 mL-0.6 mL) at 23° C.was added NaI (3.4 mg, 0.023 mmol, 0.1 equiv), K₂CO₃ (127 mg, 0.92 mmol,4.0 equiv), and 2-chloro-N,N-diethylethanamine (40 mg, 0.23 mmol, 1.0equiv). After stirring for 1.5 h at 90° C., the reaction mixture wascooled to 23° C. and CH₂Cl₂ (1 mL) was added. The phases were separatedand the aqueous phase was extracted with CH₂Cl₂ (3×1 mL). The combinedorganic phases were washed with brine (3 mL) and dried (MgSO₄). Thefiltrate was concentrated in vacuo and the residue was purified bypreparative TLC eluting with hexanes/EtOAc 1:1 to afford 65 mg of thetitle compound as colorless oil (61% yield). R_(f)=0.35 (hexanes/EtOAc7:3 (v/v)). NMR Spectroscopy: ¹H NMR (300 MHz, CDCl₃, 23° C., δ): 8.13(d, J=1.8 Hz, 1H), 8.00 (dd, J=8.7 Hz, 1.8 Hz, 1H), 7.48 (d, J=7.8 Hz,1H), 7.33 (d, J=7.5 Hz, 1H), 7.29 (dd, J=7.8 Hz, 7.5 Hz, 1H), 7.20 (dd,J=7.8 Hz, 7.5 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 4.24 (t, J=6.0 Hz, 2H),2.97 (t, J=6.0 Hz, 2H), 2.89 (t, J=8.1 Hz, 2H), 2.68 (q, J=6.9 Hz, 4H),1.82-1.70 (m, 2H), 1.41-1.30 (m, 2H), 1.08 (t, J=6.9 Hz, 6H), 0.90 (t,J=7.2 Hz, 3H). ¹⁹F NMR (281 MHz, CDCl₃, 23° C., δ): −62.90 (m, 3F).

Example 4 Synthesis of(2-butylbenzofuran-3-yl)(4-(2-(diethylamino)ethoxy-d₁₄)-3-(trifluoromethyl)phenyl)methanone(15)

Under air,(2-butylbenzofuran-3-yl)(4-hydroxy-3-(trifluoromethyl)phenyl)methanone(82 mg, 0.23 mmol, 1.0 equiv) in toluene-H₂O (1.2 mL-0.6 mL) at 23° C.is added NaI (3.4 mg, 0.023 mmol, 0.1 equiv), K₂CO₃ (127 mg, 0.92 mmol,4.0 equiv), and 2-chloro-N,N-diethylethanamine-d₁₄ (0.23 mmol, 1.0equiv). After stirring for 1.5 h at 90° C., the reaction mixture iscooled to 23° C. and CH₂Cl₂ (1 mL) is added. The phases are separatedand the aqueous phase is extracted with CH₂Cl₂ (3×1 mL). The combinedorganic phases are washed with brine (3 mL) and dried (MgSO₄). Thefiltrate is concentrated in vacuo and the residue is purified bypreparative TLC eluting with hexanes/EtOAc 1:1 to afford the titlecompound 15.

Example 5 Testing for Cardiac Ion Channel Activity

Compounds of the present invention were tested for their anti-arrhythmicactivity in a series of in vitro cardiac ion channel assays using clonedhuman channels expressed in CHO cells or HEK293 cells:

-   -   1. Cloned L-type calcium channels (hCav1.2, encoded by the human        CACNA1C gene and coexpressed with the β2 subunit, encoded by the        human CACNB2 gene and the α2δ1 subunit encoded by the human        CACNA2D1 gene, in CHO cells), responsible for I_(Ca,L), high        threshold calcium current.    -   2. Cloned hERG potassium channels (encoded by the KCNH2 gene and        expressed in human embryonic kidney, HEK293, cells) responsible        for I_(Kr).    -   3. Cloned hKir2.1 potassium channels (encoded by the human KCNJ2        gene and expressed in HEK293 cells), responsible for I_(KI),        inwardly rectifying potassium current.    -   4. Cloned hKvLQT1/hminK potassium channels (encoded by the human        KCNQ1 and KCNE1 genes and coexpressed in CHO cells), responsible        for I_(Ks), slow delayed rectifier potassium current.    -   5. Cloned hKv1.5 potassium channels (encoded by the human KCNA5        gene and expressed in CHO cells), responsible for I_(Kur),        ultra-rapid delayed rectifier potassium current.    -   6. Cloned hNav1.5 sodium channels (SCN5A gene, expressed in CHO        cells).    -   7. Cloned hKir3.1/hKir3.4 potassium channels (expressed by the        human KCNJ3 and KCNJ5 genes and co-expressed in HEK293 cells)        responsible for I_(ACh), inwardly rectifying potassium current.

One concentration of a compound of the present invention was applied fora five-minute interval via disposable polyethylene micropipette tips tonaïve cells (n≧2, where n=the number cells/concentration). Each solutionexchange, performed in quadruplicate, consisted of aspiration andreplacement of 45 μL volume of the extracellular well of the Sealchip₁₆.Duration of exposure to the test compound was three minutes. For thehKir3.1/hKir3.4 assay, two concentrations of a compound of the presentinvention were used and the duration of exposure was 3 minutes.

In preparation for an automated patch clamp procedure recording session,intracellular solution was loaded into the intracellular compartments ofthe Sealchip₁₆ or Qplate planar electrode. Cell suspension was pipettedinto the extracellular compartments of the Sealchip₁₆ or Qplate planarelectrode. After establishment of a whole-cell configuration, membranecurrents were recorded using dual-channel patch clamp amplifiers in thePatchXpress® or Qpatch HT® system. Before digitization, the currentrecords were low-pass filtered at one-fifth of the sampling frequency.

Valid whole-call recordings met the following criteria:

-   -   1. Membrane resistance (Rm)≧200 MΩ    -   2. Leak current ≦25% channel current.        hCav1.2 Test Procedure

Onset and steady state block of hCav1.2/β2/α2δ channels were measuredusing a stimulus voltage pattern consisting of a depolarizing test pulse(duration, 200 ms; amplitude, 10 mV) at 10 intervals from a −80 mVholding potential. Peak current was measured during the step to 10 mV.Saturating concentration of positive control, nifedipine (10 μM), wasadded at the end of each experiment to block hCav1.2 current. Leakagecurrent was digitally subtracted from the total membrane current record.

hERG Test Procedure

Onset and block of hERG current was measured using a stimulus voltagepattern consisting of a 500 ms prepulse to −40 mV (leakage subtraction),a 2-second activating pulse to +40 mV, followed by a 2-second test pulseto −40 mV. Leakage current was calculated from the current amplitudeevoked by the prepulse and subtracted from the total membrane currentrecord.

hKir2.1 Test Procedures

Onset and steady state block of hKir2.1 current was measured using apulse pattern with fixed amplitudes (hyperpolarization: −110 mVamplitude, 300 ms duration) repeated at 10 s intervals from a holdingpotential of −70 mV. Current amplitude was measured at the end of thestep to −110 mV.

hKvLQT1/hminK Test Procedures

Onset and steady state block of hKvLQT1/hminK current was measured usinga pulse pattern with fixed amplitudes (depolarization: +40 mV for 2 s;repolarization: −40 mV for 0.5 s) repeated at 15 s intervals from aholding potential of −80 mV. Current amplitude was measured at the endof the step to +40 mV. Saturating concentration of positive control,chromanol 293B (300 μM), was added at the end of each experiment toblock hKvLQT1/hminK current. Leakage current was measured afterchromanol 293B addition and subtracted from the total membrane currentrecord.

hKv1.5 Test Procedure

Onset and steady state block of hKv1.5 current was measured using apulse pattern with fixed amplitudes (depolarization: +20 mV amplitude,300 ms duration) repeated at 10 s intervals from a holding potential of−80 mV. Current amplitude was measured at the end of the step to +20 mV.

hNav1.5 Test Procedure

Onset and steady-state block of hNav1.5 current was measured usingdouble pulse pattern consisting of a series of two depolarizing testpulses to −15 mV. From a holding potential of −80 mV, an initialhyperpolarizing conditioning pre-pulse (−120 mV amplitude, 200 msduration,) was followed immediately by the first depolarizing test pulseto −15 mV (200 ms duration). This was followed by a hyperpolarizingconditioning inter-pulse to −80 mV (200 ms duration) and then a seconddepolarizing test pulse to −15 mV for 20 ms. The pulse pattern wasrepeated at 10 s intervals and peak current amplitudes at both testpulses were measured.

hKir3.1/hKir3.4 Test Procedure

The in vitro effects of the compounds of the present invention wereevaluated at room temperature using the PatchXpress (Model 7000A,Molecular Devices, Union City, Calif.), an automated parallel patchclamp system.

Table 3 shows the cardiac ion channel inhibition data for compoundssynthesized in Examples 1, 2, and 3.

TABLE 3 Ion Channel Amioda- Compound Compound Compound @10 μM rone 1 2 3Nav1.5 tonic  6.8% 11.5%  23%  48% Nav1.5 phasic   44%   26%  44%  86%Cav1.2  7.7%  101%  81%   2% hERG   65%   55%  75%  74% Kv1.5  0.7%  54%  21%  25% Kir2.1  0.9%  0.3% 2.7% 9.7% KvLQT −0.6%   49% 2.5% 8.4%K(ach)   23%   49% 4.6%  11% K(ach) @1 μM  4.5%   16% 1.4% 2.1%

What is claimed:
 1. A compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein X₁,X₂, X₃, and X₄ are each independently selected from hydrogen, I, F, CF₃,CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F, provided that at least one of X₁,X₂, X₃, and X₄ is F or a group of atoms containing at least one fluorineatom.
 2. The compound of claim 1, wherein at least one of X₁, X₂, X₃,and X₄ is selected from F, CF₃, CHF₂, or CH₂F.
 3. The compound of claim1, wherein one of X₁, X₂, X₃, and X₄ is selected from F, CF₃, CHF₂,CH₂F, OCF₃, OCHF₂, and OCH₂F and the remaining X₁, X₂, X₃, and X₄ areselected from F, I and hydrogen.
 4. The compound of claim 1, wherein twoof X₁, X₂, X₃, and X₄ are selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂,and OCH₂F and the remaining X₁, X₂, X₃, and X₄ are selected from F, Iand hydrogen.
 5. The compound of claim 1 of formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein X₂ isselected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;and X₃ is selected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂,and OCH₂F, provided that at least one of X₂ and X₃ is F or a group ofatoms containing at least one fluorine atom.
 6. The compound of claim 5,wherein X₂ is CF₃ and X₃ is selected from hydrogen, I, F, CF₃, CHF₂,CH₂F, OCF₃, OCHF₂, and OCH₂F.
 7. The compound of claim 5, wherein X₂ isCF₃ and X₃ is selected from hydrogen, I, F, CF₃, CHF₂, and CH₂F.
 8. Thecompound of claim 5, wherein X₂ is CF₃ and X₃ is selected from hydrogen,I, and CF₃.
 9. The compound of claim 5, wherein X₂ is F and X₃ isselected from hydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F.10. The compound of claim 5, wherein X₃ is CF₃ and X₂ is selected fromhydrogen, I, F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F.
 11. Thecompound of claim 5, wherein X₃ is CF₃ and X₂ is selected from CF₃,CHF₂, and CH₂F.
 12. The compound of claim 5, wherein X₃ is hydrogen andX₂ is selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F.
 13. Thecompound of claim 12, wherein X₃ is hydrogen and X₂ is selected from F,CF₃, CHF₂, and CH₂F.
 14. The compound of claim 1 of formula VII:

or a pharmaceutically acceptable salt thereof, wherein X₂ is selectedfrom F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F;
 15. The compound ofclaim 14, wherein X₂ is selected from F, CF₃, CHF₂, and CH₂F.
 16. Acompound of claim 1 selected from Compound # 1

2

3

4

5

6

7

8

9

10

11

12

13

14

or a pharmaceutically acceptable salt or solvate thereof.
 17. Apharmaceutical composition comprising at least one compound of claim 1or a pharmaceutically acceptable salt or solvate thereof and one or morepharmaceutically acceptable carrier or excipient.
 18. A method oftreating or preventing a pathological syndrome of the cardiovascularsystem, angina pectoris, hypertension, arrhythmias, or cerebralcirculatory insufficiency in a subject comprising administering to asubject in need thereof an effective amount of a compound of claim 1 ora pharmaceutically acceptable salt or solvate thereof.
 19. A deuteriumlabeled compound of claim 1 or a pharmaceutically acceptable salt orsolvate thereof.
 20. A deuterium labeled compound of claim 19 that is